Evaluation of anti-fibrotic and anti-inflammatory semi-synthetic oxysterol, Oxy210, as a therapeutic drug candidate for non-alcoholic steatohepatitis

抗纤维化和抗炎半合成氧甾醇 Oxy210 作为非酒精性脂肪性肝炎候选治疗药物的评价

• 批准号: 10697132
• 负责人: FARHAD PARHAMI
• 金额: $ 89.7万
• 依托单位: MAX BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10697132
• 关键词: Actins; Acute; Affect; Agonist; Alcoholic Fatty Liver; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptosis; Atherosclerosis; Award; CETP gene; COL1A1 gene; California; Cardiovascular Diseases; Cells; Cholesterol; Chronic; Circulation; Cirrhosis; Collagen; Deposition; Development; Diabetes Mellitus; Diet; Disease; Drug Kinetics; Endocrinology; Endogenous Factors; Erinaceidae; Esterification; Evaluation; Exposure to; FDA approved; Family; Fatty acid glycerol esters; Fibrosis; Future; Gene Expression; Genotype; Grant; Guidelines; Health; Hepatic; Hepatic Stellate Cell; Hepatocyte; Human; Hyperlipidemia; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inhibition of Apoptosis; Injury; Investigation; Kidney; Lead; Ligands; Lipids; Liver; Liver Failure; Liver Fibrosis; Lung; Macrophage; Manuscripts; Mediating; Medical; Medicine; Metabolic; Metabolism; Molecular; Molecular Mechanisms of Action; Morbidity - disease rate; Mus; Myofibroblast; National Institute of Diabetes and Digestive and Kidney Diseases; Oncology; Oral; Oral Administration; Organ; Orthopedics; Pathogenesis; Pathologic; Pathology; Pathway interactions; Phase; Phenotype; Phosphorylation; Population; Predisposition; Prevention; Primary carcinoma of the liver cells; Proliferating; Property; Protein-Lysine 6-Oxidase; Public Health; Publishing; Publishing Peer Reviews; Receptor Signaling; Reporting; Role; Safety; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Smooth Muscle; Structure-Activity Relationship; TGFB1 gene; TLR2 gene; TLR4 gene; Testing; Therapeutic; Tissues; Toll-like receptors; Toxicokinetics; Toxicology; Transforming Growth Factor beta; Tyrosine Kinase Receptor Inhibition; Virus Diseases; alcohol exposure; analog; antagonist; apolipoprotein E-3; clinically significant; connective tissue growth factor; culture plates; cytokine; drug candidate; efficacy evaluation; fatty liver disease; humanized mouse; improved; in vivo; inhibitor; kinase inhibitor; liver injury; liver transplantation; mortality; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel drug class; pandemic disease; patient population; pre-clinical; response; safety study; small molecule; stellate cell; therapeutic development; tissue culture; transcriptome sequencing; western diet; wound healing

ABSTRACT Pathologic tissue fibrosis, impelled by uncontrolled wound healing responses to acute or chronic injury is a significant problem in many organs including kidney, lung, and liver. Liver fibrosis is a major health problem that causes morbidity and mortality in the affected patient population. Liver fibrosis occurs in various pathologies including chronic alcohol exposure, non-alcoholic fatty liver disease (NAFLD) that can lead to non- alcoholic steatohepatitis (NASH), and viral infection, and can lead to cirrhosis and hepatocellular carcinoma. A number of molecular mechanisms have been scrutinized to identify the root causes of liver fibrosis. Among these, prominent studies point to aberrant Hedgehog (Hh) and transforming growth factor-β (TGF-β) signaling as prime factors underlying the pathogenesis of liver fibrosis, and hence extensively investigated. Accumulating evidence also suggests the role of Toll-Like Receptors (TLRs) in mediating the inflammatory responses of liver cells to endogenous factors and bacterial products present in the liver in NAFLD and NASH. At MAX BioPharma, we have identified semi-synthetic oxysterols that act as Hh pathway modulators, both as agonists and antagonists. We found oxysterol Hh pathway antagonists that also have potent inhibitory effects on TGF-β signaling in fibroblastic cells and in primary human hepatic stellate cells (HSC). With support from an SBIR Phase 1 grant from NIDDK, we recently published findings about the anti-NASH properties of an oxysterol analogue, Oxy210, that has led to the present application. Oxy210 has anti-fibrotic as well as anti- inflammatory properties that are mediated through inhibition of Hh, TGF-β and TLR signaling. Oxy210 induced robust inhibitory effects in a humanized hyperlipidemic mouse model of NASH, ApoE*3-Leiden.CETP mice on a high fat Western Diet, evidenced by inhibition of hepatic lipid deposition, inflammatory cytokine expression and fibrosis, associated with reduced hepatic cell apoptosis and improved circulating ALT levels. Based on these properties of Oxy210, in addition to its favorable pharmacokinetic and safety profiles, oral availability, and scalability, in the present SBIR Phase 2 application we propose to continue the examination of the disease modifying effects of Oxy210 in ApoE*3-Leiden.CETP mice in reversing already established disease in contrast to our published report when Oxy210 was administered at the initiation of the disease. We propose to identify the molecular and cellular mechanisms of anti-NASH properties of Oxy210 by performing metabolic tests as well as RNA-sequencing studies in livers of NASH mice with or without Oxy210 treatment. We propose to perform non-GLP in vitro and in vivo safety studies that will provide essential information for future IND-enabling GLP studies required in our anticipated IND filing for Oxy210 as a first-in-class new drug candidate for targeting NASH. NASH is a huge unmet medical need since there are no FDA approved therapies, leaving a large global population susceptible to severe liver failure and the need for liver transplantation.

抽象的 病理组织纤维化，因对急性或慢性损伤的伤口愈合反应而促使纤维化是一种 包括肾脏，肺和肝脏在内的许多器官中的重大问题。肝纤维化是一个主要的健康问题 这会导致受影响患者人群的发病率和死亡率。肝纤维化发生在各种 病理学，包括慢性酒精暴露，非酒精性脂肪肝病（NAFLD），可能导致非 - 酒精性脂肪性肝炎（NASH）和病毒感染，可导致肝硬化和肝细胞癌。一个 已经仔细检查了分子机制的数量，以识别肝纤维化的根本原因。其中， 重要的研究指出异常的刺猬（HH）和转化生长因子-β（TGF-β）信号作为素数 肝纤维化发病机理的基础，并进行了广泛研究。积累证据 还表明了Toll样受体（TLR）在介导肝细胞炎症反应中的作用 NAFLD和NASH的肝脏中存在内源性因素和细菌产物。 在Max Biopharma，我们已经确定了充当HH途径调节剂的半合成氧甲醇，既是 激动剂和对手。我们发现氧蛋白酶HH途径拮抗剂也具有潜在的抑制作用 在成纤维细胞和原代人肝星状细胞（HSC）中的TGF-β信号传导上。在来自 NIDDK的SBIR 1阶段赠款，我们最近发表了有关抗Nash特性的发现 氧化酚类似物，Oxy210，导致了当前的应用。 Oxy210具有抗纤维化和抗 通过抑制HH，TGF-β和TLR信号传导介导的炎症特性。 oxy210诱导 NASH的人性化高脂小鼠模型，ApoE*3- leiden.cetp小鼠在人源化的高脂小鼠模型中的强大抑制作用 高脂肪西方饮食，通过抑制肝脂质沉积，炎症细胞因子表达证明 和纤维化，与肝细胞凋亡降低和循环ALT水平提高有关。基于 Oxy210的这些特性，除了具有良好的药代动力学和安全性概况，口服可用性以及 可伸缩性，在当前的SBIR第2阶段应用中，我们建议继续检查该疾病 oxy210在apoe*3- leiden.cetp小鼠反向已经确立的疾病中的修改作用与 当Oxy210开始时，我们发表的报告是在疾病开始时的。我们建议确定 通过进行代谢检验的抗纳什210的抗NASH特性的分子和细胞机制 作为在有或没有OXY210治疗的NASH小鼠生计中进行的RNA测序研究。我们建议执行 非GLP体外和体内安全研究，将为未来的GLP提供必要的信息 在我们预期的IND申请oxy210中需要的研究是针对目标的第一类新药候选者 纳什。纳什（Nash）是巨大的未满足医疗需求，因为没有FDA批准的疗法 全球人口容易受到严重的肝衰竭和肝移植的需求。